1,4 substituted piperidinyl NMDA/NR2B antagonists

ABSTRACT

Novel piperidinyl compounds substituted in the 1- and 4-positions are effective as NMDA NR2B antagonists useful for relieving pain.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to novel 1,4 substituted piperidines. Inparticular, this invention relates to piperidines substituted in the 1-and 4-positions, through a bridge, with i) optionally substituted2-benzimidazoles, 2-indoles, 2-quinazolines, or 2-imidazopyridines; orii) phenyl or substituted phenyl that are effective as NMDA NR₂Bantagonists useful for relieving pain.

[0003] Ions such as glutamate play a key role in processes related tochronic pain and pain-associated neurotoxicity—primarily by actingthrough N-methyl-D-aspartate (“NMDA”) receptors. Thus, inhibition ofsuch action—by employing ion channel antagonists, particularly NMDAantagonists—can be beneficial in the treatment and control of pain.

[0004] Known NMDA antagonists include ketamine, dextromophan, and3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (“CPP”). Althoughthese compounds have been reported (J. D. Kristensen, et al., Pain,51:249-253 (1992); K. Eide, et al., Pain, 61:221-228 (1995); D. J. Knox,et al., Anaesth. Intensive Care 23:620-622 (1995); and M. B. Max, etal., Clin.Neuropharmacol. 18:360-368 (1995)) to produce symptomaticrelief in a number of neuropathies including postherpetic neuralgia,central pain from spinal cord injury, and phantom limb pain, widespreaduse of these compounds is precluded by their undesirable side effects.Such side effects at analgesic doses include psychotomimetic effectssuch as dizziness, headache, hallucinations, dysphoria, and disturbancesof cognitive and motor function. Additionally, more severehallucinations, sedation, and ataxia are produced at doses onlymarginally higher than analgesic doses. Thus, it would be desirable toprovide novel NMDA antagonists that are absent of undesirable sideeffects or that produce fewer and/or milder side effects.

[0005] NMDA receptors are heteromeric assemblies of subunits, of whichtwo major subunit families designated NR₁ and NR₂ have been cloned.Without being bound by theory, it is generally believed that the variousfunctional NMDA receptors in the mammalian central nervous system(“CNS”) are only formed by combinations of NR₁ and NR₂ subunits, whichrespectively express glycine and glutamate recognition sites. The NR₂subunit family is in turn divided into four individual subunit types:NR₂A, NR₂B, NR₂C, and NR₂D. I. Ishii, et al., J. Biol. Chem.,268:2836-2843 (1993), A. Wenel, et al., Neural Report, 7:45-48 (1995),and D. J. Laurie et al., Mol. Brain Res., 51:23-32 (1997) describe howthe various resulting combinations produce a variety of NMDA receptorsdiffering in physiological and pharmacological properties such as iongating properties, magnesium sensitivity, pharmacological profile, aswell as in anatomical distribution.

[0006] For example, while NR₁ is found throughout the brain, NR₂subunits are differentially distributed. In particular, it is believedthat the distribution map for NR₂B lowers the probability of sideeffects while producing pain relief. For example, S. Boyce, et al.,Neuropharmacology, 38:611-623(1999) describes the effect of selectiveNMDA NR₂B antagonists on pain with reduced side-effects. Thus, it wouldbe desirable to provide novel NMDA antagonists that target the NR₂Breceptor.

[0007] Phenol compounds described as NMDA antagonists are described inU.S. Pat. Nos. 5,306,723 and 5,436,255, and in International PatentPublications WO91/17156, WO92/19502, WO93/02052, WO94/29571, WO95/28057,WO96/37226, and EP 04422506. Benzyl piperidine substituted with phenolsor imidazoles are described in Z. -L. Zhou, et al., J. MedicinalChemistry, 42:2993-3000(1999); T. F. Gregory, et al., Poster #94,218^(th) National Meeting American Chemical Society, New Orleans, La.,Aug. 22-26, 1999. Other NMDA NR₂B selective compounds are described inEuropean Patent Publication EP 787493 and British J.Pharmacol.,123:463(1998). However, there continues to be a need for novel NMDAantagonists that target the NR₂B receptor.

[0008] International Patent Publication WO94/21615 describesbenzimidazole-piperidine compounds utilized as dopamine D4 antagonists.

SUMMARY OF THE INVENTION

[0009] The present invention relates to novel piperidines substituted inthe 1- and 4-positions, through a bridge, with i) optionally substituted2-benzimidazoles, 2-indoles, 2-quinazolines, or 2-imidazopyridines; orii) phenyl or substituted phenyl. The present invention also formspharmaceutical compositions utilizing the compounds. Further, thisinvention includes novel methods to treat pain by utilizing thecompounds.

DETAILED DESCRIPTION OF THE INVENTION

[0010] In one aspect, the compounds of this invention are represented byFormula (I):

[0011] or pharmaceutically acceptable salts thereof, wherein

[0012] R₁ is i) 2-benzimidazole, 2-imidazopyridine, 2-indole, purine, or2-quinazoline, each optionally substituted with one to fivesubstituents, each substituent independently being chloro, fluoro,bromo, C₁-C₄alkyl, trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, orcarboxy; or ii) phenyl, optionally substituted with one to fivesubstituents, each substituent independently being chloro, fluoro,bromo, C₁-C₄alkyl, trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, orcarboxy;

[0013] R₂ is a) 2-benzimidazole, 2-imidazopyridine, 2-indole, purine, or2-quinazoline, each optionally substituted with one to fivesubstituents, each substituent independently being chloro, fluoro,bromo, C₁-C₄alkyl, trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, orcarboxy; or b) phenyl, optionally substituted with one to fivesubstituents, each substituent independently being chloro, fluoro,bromo, C₁-C₄alkyl, trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, orcarboxy;

[0014] When R₁ is i, then R₂ is b; when R₁ is ii, then R₂ is a;

[0015] When R₁ or R₂ is 2-benzimidazole, respective L₁ or L₂ is notC₁-C₂alkyl, except when R₁ or R₂ is hydroxy-substituted 2-benzimidazole,respective L₁ or L₂ includes C₁-C₂alkyl

[0016] L₁ and L₂ are independently C₁-C₄alkyl, C₁-C₄alkenyl,C₁-C₄alkynyl, C₁-C₄alkoxy, aminoC₁-C₄alkyl, hydroxyC₁-C₄alkyl, carbonyl,cycloC₃-C₆alkyl or aminocarbonyl; and

[0017] optionally substituted at any of the 2, 3, 5, or 6 positionsindependently with X, wherein X is hydroxy, amino, C₁-C₄alkylamino,di(C₁-C₄)alkylamino, C₁-C₄alkyl, ester, carbamate, carbonate, or ether.

[0018] In an embodiment of this invention the compound is represented byFormula (I) or a pharmaceutically acceptable salt thereof, wherein

[0019] R₁ is 2-imidazopyridine, optionally substituted with one to fivesubstituents, each substituent independently being chloro, fluoro,bromo, C₁-C₄alkyl, trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, orcarboxy;

[0020] R₂ is phenyl, optionally substituted with one to fivesubstituents, each substituent independently being chloro, fluoro,bromo, C₁-C₄alkyl, trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, orcarboxy;

[0021] L₁ and L₂ are independently C₁-C₄alkyl, C₁-C₄alkenyl,C₁-C₄alkynyl, C₁-C₄alkoxy, aminoC₁-C₄alkyl, hydroxyC₁-C₄alkyl, carbonyl,cycloC₃-C₆alkyl or aminocarbonyl; and

[0022] optionally substituted at any of the 2, 3, 5, or 6 positionsindependently with X, wherein X is hydroxy, amino, C₁-C₄alkylamino,di(C₁-C₄)alkylamino, C₁-C₄alkyl, ester, carbamate, carbonate, or ether.

[0023] In another embodiment of this invention the compound isrepresented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

[0024] R₁ is purine, optionally substituted with one to fivesubstituents, each substituent independently being chloro, fluoro,bromo, C₁-C₄alkyl, trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, orcarboxy;

[0025] R₂ is phenyl, optionally substituted with one to fivesubstituents, each substituent independently being chloro, fluoro,bromo, C₁-C₄alkyl, trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, orcarboxy;

[0026] L₁ and L₂ are independently C₁-C₄alkyl, C₁-C₄alkenyl,C₁-C₄alkynyl, C₁-C₄alkoxy, aminoC₁-C₄alkyl, hydroxyC₁-C₄alkyl, carbonyl,cycloC₃-C₆alkyl or aminocarbonyl; and

[0027] optionally substituted at any of the 2, 3, 5, or 6 positionsindependently with X, wherein X is hydroxy, amino, C₁-C₄alkylamino,di(C₁-C₄)alkylamino, C₁-C₄alkyl, ester, carbamate, carbonate, or ether.

[0028] In still another embodiment of this invention the compound isrepresented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

[0029] R₁ is 2-benzirmidazole, optionally substituted with one to fivesubstituents, each substituent independently being chloro, fluoro,bromo, C₁-C₄alkyl, trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, orcarboxy;

[0030] R₂ is phenyl, optionally substituted with one to fivesubstituents, each substituent independently being chloro, fluoro,bromo, C₁-C₄alkyl, trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, orcarboxy;

[0031] L₁ is not C₁-C₂alkyl, except when R₁ is hydroxy-substituted2-benzimidazole, L₁ includes C₁-C₂alkyl;

[0032] L₁ and L₂ are independently C₁-C₄alkyl, C₁-C₄alkenyl,C₁-C₄alkynyl, C₁-C₄alkoxy, aminoC₁-C₄alkyl, hydroxyC₁-C₄alkyl, carbonyl,cycloC₃-C₆alkyl or aminocarbonyl; and

[0033] optionally substituted at any of the 2, 3, 5, or 6 positionsindependently with X, wherein X is hydroxy, amino, C₁-C₄alkylamino,di(C₁-C₄)alkylamino, C₁-C₄alkyl, ester, carbamate, carbonate, or ether.

[0034] As used herein, “alkyl” as well as other groups having the prefix“alk” such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and thelike, means carbon chains which may be linear or branched orcombinations thereof. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl andthe like. “Alkenyl”, “alkynyl” and other like terms include carbonchains containing at least one unsaturated C—C bond.

[0035] The term “cycloalkyl” means carbocycles containing noheteroatoms, and includes mono-, bi- and tricyclic saturatedcarbocycles, as well as fused ring systems. Such fused ring systems caninclude one ring that is partially or fully unsaturated such as abenzene ring to form fused ring systems such as benzofused carbocycles.Cycloalkyl includes such fused ring systems as spirofused ring systems.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl;cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl,fluorenyl, 1,2,3,4-tetrahydronaphalene and the like. Similarly,“cycloalkenyl” means carbocycles containing no heteroatoms and at leastone non-aromatic C—C double bond, and include mono-, bi- and tricyclicpartially saturated carbocycles, as well as benzofused cycloalkenes.Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.

[0036] Unless otherwise stated, the terms “carbonyl” and “aminocarbonyl”include short C₁-C₂ termini. The terms include, for example, —CH₂CONH—,—CH₂CO—, —C₂H₄CONHCH₂—, and —CH₂COC₂H₄—.

[0037] Unless otherwise stated, the term “carbamate” is used to include—OCOOC₁—C₄alkyl, —NHCOOC₁—C₄alkyl, and —OCONHC₁—C₄alkyl.

[0038] The term “halogen” includes fluorine, chlorine, bromine andiodine atoms.

[0039] The term “SEM” is used to describe —CH₂—O—CH₂CH₂—Si(CH₃)₃.

[0040] The term “Co” means that the carbon is not present. Thus, “C₀-C₅”means that there are from none to five carbons present—that is, five,four, three, two, one, or no carbons present.

[0041] The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring.

[0042] Compounds described herein contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

[0043] The term “pharmaceutically acceptable salts” refers to saltsprepared from pharmaceutically acceptable non-toxic bases or acids. Whenthe compound of the present invention is acidic, its corresponding saltcan be conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

[0044] When the compound of the present invention is basic, itscorresponding salt can be conveniently prepared from pharmaceuticallyacceptable non-toxic acids, including inorganic and organic acids. Suchacids include, for example, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

[0045] The pharmaceutical compositions of the present invention comprisea compound represented by Formula I (or pharmaceutically acceptablesalts thereof) as an active ingredient, a pharmaceutically acceptablecarrier and optionally other therapeutic ingredients or adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

[0046] In practice, the compounds represented by Formula I, orpharmaceutically acceptable salts thereof, of this invention can becombined as the active ingredient in intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,oral or parenteral (including intravenous). Thus, the pharmaceuticalcompositions of the present invention can be presented as discrete unitssuitable for oral administration such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient.Further, the compositions can be presented as a powder, as granules, asa solution, as a suspension in an aqueous liquid, as a non-aqueousliquid, as an oil-in-water emulsion or as a water-in-oil liquidemulsion. In addition to the common dosage forms set out above, thecompound represented by Formula I, or pharmaceutically acceptable saltsthereof, may also be administered by controlled release means and/ordelivery devices. The compositions may be prepared by any of the methodsof pharmacy. In general, such methods include a step of bringing intoassociation the active ingredient with the carrier that constitutes oneor more necessary ingredients. In general, the compositions are preparedby uniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

[0047] Thus, the pharmaceutical compositions of this invention mayinclude a pharmaceutically acceptable carrier and a compound or apharmaceutically acceptable salt of Formula I. The compounds of FormulaI, or pharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

[0048] The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

[0049] In preparing the compositions for oral dosage form, anyconvenient pharmaceutical media may be employed. For example, water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like may be used to form oral liquid preparations such assuspensions, elixirs and solutions; while carriers such as starches,sugars, microcrystalline cellulose, diluents, granulating agents,lubricants, binders, disintegrating agents, and the like may be used toform oral solid preparations such as powders, capsules and tablets.Because of their ease of administration, tablets and capsules are thepreferred oral dosage units whereby solid pharmaceutical carriers areemployed. Optionally, tablets may be coated by standard aqueous ornonaqueous techniques

[0050] A tablet containing the composition of this invention may beprepared by compression or molding, optionally with one or moreaccessory ingredients or adjuvants. Compressed tablets may be preparedby compressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 1 mg to about 500 mg of the activeingredient and each cachet or capsule preferably containing from about 1to about 500 mg of the active ingredient.

[0051] Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

[0052] Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

[0053] Pharmaceutical compositions of the present invention can be in aform suitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment-is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

[0054] Pharmaceutical compositions of this invention can be in a formsuitable for rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

[0055] In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

[0056] Experimental Protocols

Assessing the Activity of Selected Compounds to Inhibit NR₁A/2B NMDAReceptor Activation (FLIPR Assay)

[0057] The activity of selected compounds to inhibit NR1A/2B NMDAreceptor activation measured as NR₁A/2B receptor-mediated Ca²⁺ influx isassessed by the following procedure:

[0058] NR1A/2B receptor transfected L(tk) cells are plated in 96-wellformat at 3×10⁶ cells per plate and grown for one—two days in normalgrowth media (Dulbeccos MEM with Na pyruvate, 4500 mgglucose, pen/strep,glutarine, 10% FCS and 0.5 mg/ml geneticin). NR1A/2B-expression in thesecells is induced by the addition of 4 nM dexamethasone in the presenceof 500 μM ketamine for 16-24 hours. After receptor induction cells arewashed using a Labsystem Cellwasher two times with assay buffer (Hanksbalanced salt solution (HBSS-Mg⁺⁺ free) containing 20 mM HEPES, 0.1%BSA, 2 mM CaCl₂ and 250 μM probenecid). The cells of each 96 well cellplate are loaded with the Ca⁺⁺ sensitive dye Fluo-3 (Molecular Probes,Inc.) at 41M in assay buffer containing 0.5% FBS, and 0.04% pluronicF-127 (Molecular Probes, Inc.) for 1 h at 37° C. avoiding light. Thecells are then washed with the Cellwasher four times with assay bufferleaving them in 100 μl buffer. Test compounds in solution are pipettedby FLIPR (Fluorometric Imaging Plate Reader) into each test well for a 2min pretreatment. During this time the fluorescence intensity isrecorded (excitation at 488 nm and emission at 530 nm). Theglutamate/glycine 50 μl agonist solution (final concentration 1 μM/1 μM)is then added by FLIPR into each well already containing 150 μl ofbuffer (containing the test compound or vehicle) and the fluorescence iscontinuously monitored for 10 min. The endpoint fluorescence values areused to determine an IC₅₀ value comparing the agonist-stimulated signalfor the vehicle alone sample and that for the cells incubated with eachconcentration of test compound.

Determining the Apparent Dissociation Constant (Ki) of Compounds forHuman NR1A/NR₂B Receptors (Binding Assay)

[0059] The radioligand binding assay is performed at room temperature in96-well microtiter plates with a final assay volume of 1.0 mL in 20 mMHepes buffer (pH 7.4) containing 150 mM NaCl. Solutions of testcompounds were prepared in DMSO and serially diluted with DMSO to yield20 μL of each of 10 solutions differing by 3-fold in concentration.Non-specific binding (NSB) using hot AMD-1 (10 μM final concentration)and total binding (TB) by using DMSO (2% final concentration). Asolution of NR1A/NR₂B receptors (40pM final concentration) and tritiatedAMD-2 (1 nM final concentration) were added to the test compounds. After3 h of incubation at room temperature, samples are filtered throughPackard GF/B filters (presoaked in 0.05% PEI, polyethyleninine SigmaP-3143) and washed 10 times with imL of cold 20 mM Hepes buffer perwash. After vacuum drying of the filter plates, 40 μL of PackardMicroscint-20 was added and bound radioactivity determined in a PackardTopCount. The apparent dissociation constant (Ki), the maximumpercentage inhibition (% I_(max)), the minimum percentage inhibition (%I_(min)) and the hill slope (nH) were determined by a non-linear leastsquares fitting the bound CPM data to Equation #1 below.${{E\quad q\quad u\quad a\quad t\quad i\quad o\quad n\quad {\# 1}}:\quad {{CPM}\quad B\quad o\quad u\quad n\quad d}} = {\frac{\left( {S\quad B} \right)\left( {{\% \quad I_{\max}} - {\% \quad I_{\min}}} \right)}{\left( {1 + \left( \quad {\left\lbrack {D\quad r\quad u\quad g} \right\rbrack/\left( {K\quad {{i\left\lbrack {L - {844,345}} \right\rbrack}/K_{D}}} \right)} \right)^{n\quad H}} \right)} + {N\quad S\quad B} + {\left( {S\quad B} \right)\left( {1 - {\% \quad I_{\max}}} \right)}}$

[0060] where, K_(D) is the apparent dissociation constant for theradioligand for the receptor as determined by hot saturation and SB isthe specifically bound CPM determined from the difference of TB and NSB.

[0061] Compounds AMD-1 and AMD-2 can be synthesized in accordance withthe following general reaction schemes.

[0062] In accordance with scheme 1, hydrogen chloride is bubbled througha solution of the appropriately substituted benzonitrile 1 in methanolat room temperature. The volatiles are removed under reduced pressureand the resulting residue is triturated with ether and filtered to yieldthe desired imidate 2. Imidate 2 is dissolved in methanol at ambienttemperature, treated with amine 3 at ambient temperature and stirredunder argon. The volatiles are removed under reduced pressure and theresidue purified by preparative HPLC or trituration with ether to affordamidine Ia.

[0063] In accordance with scheme 2, at room temperature under argon,amine 3a is dissolved in ether and was treated with 1-M hydrogenchloride in ether (1 equiv.) in a single portion. The resultingprecipitate is stirred vigorously for 10 minutes. The volatiles areremoved under reduced pressure. The residue is suspended in toluene,cooled to 0° C. under argon, treated with 2.0-M trimethylaluminum (1.05equiv.) in a dropwise manner, and stirred for 45 minutes at roomtemperature to afford intermediate 6 (not isolated). Compound 6 is addedto a solution of nitrile 1 in toluene. The reaction is heated to 80° C.without stirring in a sealed tube for 18 h, cooled to ambienttemperature, poured onto a silica gel column and eluted withmethanol/dichloromethane to give the amidine 4.

[0064] Tritiated AMD-1 was prepared by the following procedure: Amixture of AMD-1, hydrochloride salt, (5 mg, 0.012 mmol) in dioxane (0.2mL) containing triethylamine (4 μL) was treated with hexamethylditin (5μL), a catalytic amount of palladium catalyst and heated at 100° C. for45 minutes. The reaction was cooled to room temperature, filteredthrough a glass wool plug, rinsed with methanol and concentrated invacuo to give 10.7 mg of a brown oil. The oil was dissolved in methylenechloride and passed through a small silica column eluting with methylenechloride followed by 5% methanol/methylene chloride. Fractionscontaining the trimethylstannane (Rf 0.26 in 10% methanol/methylenechloride) were pooled and concentrated in vacuo to give 4.5 mg of thetrimethylstannane as a clear colorless oil. This material was furtherpurified by HPLC (C18 Econosil, 10×250 mm, 20 minute linear gradient,30% MeCN:70% H₂O (0.1% TFA) to 90% MeCN, 3 mL/min, 254 nm, retentiontime 15 minutes) to give 3 mg of the trimethylstannane.

[0065] A Na¹²⁵I shipping vial (10 mCi, Amersham) was charged with a stirbar, an iodobead, 50 μL of methanol and stirred five minutes at roomtemperature. A solution of the trimethylstannane (0.1 mg) in 50 μL ofmethanol containing 5 μL of trifluoroacetic acid was added and thereaction was stirred for five minutes. The reaction was quenched with 50μL of ammonium hydroxide and purified by HPLC (C18 Vydac protein andpeptide column, 4.6×250 mm, 20 minute linear gradient, 30% MeCN:70% H₂O(0.1% TFA) to 90% MeCN, 1 mL/min, retention time 11 minutes). Fractionscontaining the radioactive product were pooled and concentrated in vacuoto give 989 μCi of [¹²⁵I]AMD-1 with a specific activity of 898 Ci/mmolas measured by UV absorbance at 272 nm.

Synthesis of Tritiated AMD-2

[0066] Tritiated AMD-2 was prepared by the following procedure: Thephenol of AMD-2 (2 mg, 0.008 mmol) dissolved in dimethylformamide (0.6mL) and potasium carbonate (1.2 mg) for 1 hr. High specific activitytritiated methyl iodide (50 mCi, 0.0006 mmol, in toluene 1 mL, AmericanRadiolabeled Chemicals) was added at room temperature and stirred for 2hours. The reaction mixture was filtered using a Whatman PTFE 0.45 μmsyringeless filter device to remove any insoluable potassium carbonate,washed with Abs. ethanol (2 mL, Pharmco), and the combined filtrateswere concentrated to dryness at room temperature using a rotaryevaporator; this also removed any unreacted tritiated methyl iodide. Theresidue was purified by HPLC chromatography on a Phenomenx Luna C8semi-prep column (Luna 5 micro C₈(2), 250×10.0 mm) using a gradientsystem of 20/80 acetonitrile/water with 0.1% trifluoroacetic acid to100% acetronitrile with 0.1% trifluoroacetic acid in 20 min. Totalactivity of the product was 8 mCi. Further purification was effected byabsorption onto a Waters C-18 Sep-pak column (Waters Sep-Pak PLUS C18)and elution with water followed by absolute ethanol. The product wasdiluted with absolute ethanol (10 mL) before submission for finalanalysis.

[0067] The compounds of this invention exhibit less than 50 μM in theFLIBR and binding assays. Thus, the compounds and pharmaceuticalcompositions of this invention have been found to exhibit biologicalactivity as NMDA NR2B antagonists. Accordingly, another aspect of theinvention is the treatment of pain, migraine, depression, anxiety,schizophrenia, Parkinson's disease, or stroke—maladies that are amenableto amelioration through inhibition of NMDA NR₂B receptors—by theadministration of an effective amount of the compounds of thisinvention.

[0068] The following examples are provided to more fully illustrate thepresent invention, and are not to be construed as limiting the scope ofthe claims in any manner.

EXAMPLES

[0069] The compounds of this invention can be prepared by proceduressimilar to Scheme 1 shown below but modified by the utilization of otherreactants in place of 1-SEM-benzimidole-2-carboxaldehyde.

[0070] In Scheme 1 above, in place of the1-SEM-benzimidole-2-carboxaldehyde

[0071] any of the following aldehydes or ketones can be used to preparethe compounds of this invention:

Known Example

[0072]

[0073] 2-(4-Benzyl-piperidin-1-ylmethyl)-1H-benzimidazole

[0074] Example 1 was prepared by the following procedure.

[0075] 1-(2-Trimethylsilylethoxymethyl)-1H-benzoimidazole:

[0076] A mixture of KH, from 7 g of 30% oil dispersion, and 5 g ofbenzimidazole in 100 mL of THF was stirred under nitrogen at roomtemperature for 18 h. To the stirred suspension was added 7 g of2-trimethylsilylethoxymethyl chloride and the mixture kept at roomtemperature for 24 h, cooled in an ice bath, cautiously quenched with 50mL of water, and extracted into ether. The combined ether extracts weredried over magnesium sulfate and concentrated. Low pressurechromatography over silica gel eluting with a gradient of 3:1 ethylacetate:hexane to 100% ethyl acetate gave 9.5 g of 1-SEM-benzimidazoleas a colorless oil.

[0077]1-(2-Trimethylsilylethoxymethyl)-1H-benzoimidazole-2-carbaldehyde:

[0078] To a solution of 40 mmole of lithium diisopropylamide in 100 mLof THF cooled to −78° C. was added 5 g of 1-SEM-benzimidazole in 50 mLof THF. After 1.5 h at or below −70° C., the red solution was quenchedby rapid addition of 6 mL of methyl formate. After warming to roomtemperature over 30 min, 50 mL of water and 200 mL of ethyl acetate wereadded. The organic layer was separated and dried over magnesium sulfatethen concentrated under reduced pressure to 5.3 g of a thick oil thatsolidified in the freezer.

[0079] 2-(4-Benzyl-piperidin-1-ylmethyl)-1H-benzimidazole:

[0080] A mixture of 0.5 g of 4-benzyl-piperidine, 0.5 g of1-(2-trimethylsilylethoxymethyl)-1H-benzoimidazole-2-carbaldehyde, 5 mLof 1,2-dichloroethane and 0.5 g of sodium triacetoxyborohydride wasstirred at room temperature for 48 h. The reaction mixture was dilutedwith 50 mL chloroform and 10 mL saturated aqueous Na₂CO₃ and the layersseparated. The aqueous layer was extracted with 2×25 mL of chloroformand the combined organic layers dried over magnesium sulfate andconcentrated under reduced pressure. The crude SEM ether was heated toreflux in 50 mL of ethanol containing 5 mL of 3N HCl for 2 h, cooled,concentrated and partitioned between 10 mL of saturated aqueous sodiumcarbonate and 3×25 mL of chloroform. The chloroform extracts were driedover magnesium sulfate and concentrated. Purification by chromatographyeluting with 90:10 CHCl₃:MeOH gave 0.8 g of2-[4-benzyl-piperidin-1-ylmethyl]-1H-benzimidazole: MS (m+1)=; ¹H NMR(400 MHz, CDCl₃)

Example 1

[0081]

[0082] 2-(4-Benzyl-piperidin-1-ylmethyl)-imidazo[4,5-b]pyridine

[0083] Example 1 was prepared in a similar manner to the Known Exampleabove, but substituting 3H-imidazo[4,5-b]pyridine for benzimidazole inStep 1. Purification by chromatography eluting with 90:10 CHCl₃:MeOHgave 2-(4-benzyl-piperidin-1-ylmethyl)-imidazo[4,5-b]pyridine: MS(m+1)=307.4; ¹H NMR (400 MHz, CDCl₃) 9.75 (br, 1H), 8.4 (d, 1H), 7.95(d, 1H), 7.3-7.1 (m, 5H), 3.9 (s, 2H), 2.9 (d, 2H), 2.6 (d, 2H), 2.2(dd, 2H), 1.7 (d, 2H), 1.7 (m, 1H), 1.4 (dd, 2H).

Example 2

[0084]

[0085] 8-(4-Benzyl-piperidin-1-ylmethyl)-purine

[0086] Example 2 was prepared in a similar manner to the Known Exampleabove, but substituting purine for benzimidazole in Step 1. Purificationby chromatography eluting with 90:10:1 CHCl₃:MeOH:NH40H gave8-(4-benzyl-piperidin-1-ylmethyl)-purine: MS (m+1)=308.4; ¹H NMR (400MHz, CDCl₃) 9.05 (s, 1H), 9.0 (s, 1H), 7.3-7.1 (m, 5H), 3.9 (s, 2H), 2.9(d, 2H), 2.6 (d, 2H), 2.2 (dd, 2H), 1.7 (d, 2H), 1.7 (m, 1H), 1.4 (dd,2H).

Example 3

[0087]

[0088] 2-(4-Benzyl-piperidin-1-ylmethyl)-imidazo[4,5-c]pyridine

[0089] Example 3 was prepared in a similar manner to the Known Exampleabove, but substituting 3H-imidazo[4,5-b]pyridine for benzimidazole inStep 1. Purification by chromatography eluting with 90:10:1CHCl₃:MeOH:NH4OH gave2-(4-benzyl-piperidin-1-ylmethyl)-imidazo[4,5-c]pyridine: MS(m+1)=307.4; ¹H NMR (400 MHz, CDCl₃) 9.75 (br, 1H), 8.4 (d, 1H), 7.95(d, 1H), 7.3-7.1 (m, 6H), 3.90 (s, 2H), 2.90 (d, 2H), 2.6 (d, 2H), 2.2(dd, 2H), 1.7 (d, 2H), 1.7 (m, 1H), 1.4 (dd, 2H).

Example 4

[0090]

[0091] 2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-1H-benzimidazole

[0092] Example 4 was prepared by the following procedure.

[0093] 3-(1H-Benzimidazol-2-yl)-propan-1-ol:

[0094] A mixture of 5.4 g of 1,2-phenylenediamine and 4.5 g ofdihydro-furan-2-one in 50 mL of 4N hydrochloric acid was heated toreflux for 20 h, 1 teaspoon of decolorizing carbon added, and afteranother 15 min reflux, filtered hot. The filtrate was concentrated underreduced pressure to near dryness, the residue made basic (pH=8) withsaturated sodium bicarbonate and extracted into 3×80 mL of ether. Thecombined extracts were dried over magnesium sulfate and concentratedunder reduced pressure. After drying under vacuum, 8.4 g of3-(1H-benzimidazol-2-yl)-propan-1-ol was obtained as a solid.

[0095] 3-[2-(3-Hydroxy-propyl)-benzimidazol-1-yl]-propionitrile:

[0096] To a stirred solution of 3.8 g of3-(1H-benzimidazol-2-yl)-propan-1-ol and 4 g dihydropyran in 500 mL ofTHF was added p-toluenesulfonic acid monohydrate until the pH was about3 (indicator paper). After stirring overnight, an additional 2 mL ofdihydropyran was added. After 2 additional hours, the conversion wascomplete. The mixture was concentrated under reduced pressure andpartitioned between 250 μL of 1N NaOH and 2×250 mL of ether. Afterdrying over magnesium sulfate the combined extracts were concentrated todryness.

[0097] To a solution of the resulting crude oily2-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzimidazole (14 g) in 250%Lof acetonitrile was added 5 mL of acrylonitrile, 2 drops of IMtetrabutylammonium fluoride in THF and I drop ION NaOH. After heating to85° C. for 16 h, conversion was complete (TLC elution with 90:10methylene chloride:methanol). After concentration under reducedpressure, the residue was partitioned between 2×200 mL of ethyl acetateand 200 mL of water. The combined extracts were dried over magnesiumsulfate and concentrated under reduced pressure.

[0098] The crude3-{2-[3-(tetrahydro-pyran-2-yloxy)-propyl]-benzimidazol-1-yl}-propionitrilewas stirred in 250 mL of methanol with sufficient p-toluenesulfonic acidmonohydrate to make the solution acidic (pH=1-2). After stirringovernight, the solution was concentrated under reduced pressure, madebasic (pH=8) with 1N sodium hydroxide and extracted into 8×50 mL ofethyl acetate. The aqueous layer was saturated with NaCl to aid inextraction of the product. The combined extracts were dried overmagnesium sulfate and concentrated under reduced pressure.Chromatography using a gradient of ethyl acetate then 10% methanol inethyl acetate followed by trituration with ether-hexane gave 4.8 g of3-[2-(3-hydroxy-propyl)-benzimidazol-1-yl]-propionitrile as a solid.

[0099] 3-[2-(3-Oxo-propyl)-benimidazol-1-yl]-propionitrile:

[0100] To a stirred solution of 0.5 g of oxalyl chloride in 15 mL ofmethylene chloride cooled to −78° C. was added 1 mL of anhydrous DMSO.After 15 min, a solution of 1 g of3-[2-(3-hydroxy-propyl)-benzimidazol-1-yl]-propionitrile in 50 mL ofmethylene chloride and 10 mL of anhydrous DMSO was added while keepingthe temperature below −50° C. There was considerable precipitate whichredissolved on warming to 0° C. over 20 min. After cooling back down to−50° C., 5 mL of triethyl amine was added and the mixture allowed towarm to room temperature. After 15 min, the mixture was diluted with 250mL of water, shaken and separated. The organic layer was dried overmagnesium sulfate and concentrated under reduced pressure. The crude3-[2-(3-oxo-propyl)-benimidazol-1-yl]-propionitrile was an amber resin(1 g), and contained only traces of the starting alcohol by TLC (90:10methylene chloride:methanol).

[0101]3-{2-[3-(3-Benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-benzimidazol-1-yl}-propionitrile:

[0102] A mixture of 0.25 g of 4-benzyl-piperidine, 0.4 g of1-3-[2-(3-oxo-propyl)-benimidazol-1-yl]-propionitrile, 5 mL of1,2-dichloroethane and 0.3 g of sodium triacetoxyborohydride was stirredat room temperature for 24 h. The reaction mixture was diluted with 50mL chloroform and 10 mL saturated aqueous Na₂CO₃ and the layersseparated. The aqueous layer was extracted with 2×25 mL of chloroformand the combined organic layers dried over magnesium sulfate andconcentrated under reduced pressure. Low pressure chromatography elutingwith a gradient of 70:30 ethyl acetate:methanol to 70:30:5 ethylacetate:methanol:triethylamine gave 400 mg of3-{2-[3-(4-benzyl-piperidin-1-yl)-propyl]-benzoimidazol-1-yl}-propionitrileas a gum.

[0103]2-[3-(3-Benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-1H-benzimidazole:

[0104] A mixture of 0.4 g of3-{2-[3-(4-benzyl-piperidin-1-yl)-propyl]-benzoimidazol-1-yl}-propionitrile,20 mL of isopropanol and 2 mL of 0.4 M sodium in isopropanol was heatedto reflux for 2 h. Conversion was complete by TLC (80:20:1 ethylacetate:methanol:triethylamine). The mixture was cooled, diluted with 10mL of saturated sodium bicarbonate and concentrated. The residue waspartitioned between 3×100 mL of chloroform and SOmL of water. Afterdrying over magnesium sulfate and concentration under reduced pressure,the residue was purified by preparative TLC eluting with 400:100:25ethyl acetate:methanol:triethylamine. The major band (UV visualization)was 2-[3-(4-benzyl-piperdin-1-yl)-propyl]-1H-benzimidazole (220 mg): MS(m+1)=334.2; ¹H NMR (400 MHz, CDCl₃) 7.4 (d, 2H), 7.32 (m, 2H), 7.25(m,1H), 7.2 (m, 4H), 3.1 (m, 4H), 2.65 (m, 2H), 2.6 (m, 2H), 2.1 (m,2H), 2.0 (m, 2H), 1.8 (m, 2H), 1.7 (m, 11), 1.5 (m, 2H).

Example 5

[0105]

[0106] 2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-imidazo[4,5-b]pyridine

[0107] Example 5 was prepared by the following procedure.

[0108] 4-Bromo-Butyric Acid Benzyl Ester:

[0109] To an ice cold solution of 5 g of 4-bromobutyric acid and 5.5 gof benzylchloroformate in 100 mL of dichloromethane was added 5 mL oftriethylamine and then 700 mg of 4-dimethylaminopyridine. A vigorousexothermic reaction ensued with evolution of carbon dioxide. Afterstirring for 3 h, the mixture was diluted with 100 mL of dichloromethaneand washed with 200 mL of saturated sodium bicarbonate, dried overmagnesium sulfate, and concentrated to an oil. Azeotropic drying withtoluene gave 8 g of 4-bromobutyric acid benzyl ester as a clear oil.

[0110] 4-(4-Benzyl-piperidin-1-yl)-Butyric Acid:

[0111] A mixture of 0.9 g of 4-bromobutyric acid benzyl ester, 0.5 g of4-benzylpiperidine, 0.6 mL of N,N-diisopropylethylamine and 20 mL ofacetonitrile was heated to 80° C. for 4 h. The mixture was cooled,concentrated under reduced pressure and partitioned between chloroformand saturated sodium carbonate. After drying over magnesium sulfate theextracts were concentrated to a thick oil, 1.4 g, which was a mixture ofthe benzyl ester of 4-(4-benzyl-piperidin-1-yl)-butyric acid, benzyl4-bromobutyrate and butyrolactone. Hydrogenation over 0.5 g of palladiumon carbon in 100 mL of ethanol under 1 atm of hydrogen overnight gave0.9 g of 4-(4-benzyl-piperidin-1-yl)-butyric acid after drying undervacuum at 100° C. overnight which was homogeneous by TLC (90:10:1chloroform:methanol : ammonium hydroxide).

[0112]2-[3-(3-Benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-3H-imidazo[4,5-b]pyridine:

[0113] A mixture of 0.6 g of 4-(4-benzyl-piperidin-1-yl)-butyric acid,0.25 g of 1,2-diaminopyridine and 6 g of polyphosphoric acid was heatedto 185° C. for 2 h. The mixture was cooled and stirred with 100 mL of 3Nsodium hydroxide for 1 h after becoming homogeneous. The solution wasextracted with 5×100 mL of chloroform and the combined extracts washed3×50 mL of dilute ammonium hydroxide, heated with 1 g of decolorizingcarbon for 10 min, cooled, filtered and concentrated. Purification ofthe residue by chromatography, eluting with 400:100:25 ethylacetate:methanol:triethylamine gave 210 mg of2-[3-(4-benzyl-piperidin-1-yl)-propyl]-imidazo[4,5-b]pyridine: MS(m+1)=335.2; ¹H NMR (400 MHz, CDCl₃) 8.36 (d, 1H), 7.8 (d, 1H), 7.6 (d,0.5H), 7.3-7.1 (complex, 5.5H), 6.85 (d, 0.5H), 6.6 (dd, 0.5H), 3.12(dd, 2H), 3.0 (d, 2H), 2.6 (d, 2H), 2.55 (dd, 2H), 2.0 (m, 4H), 1.7 (d,2H), 1.6 (m, 1H), 1.5 (m, 2H).

Example 6

[0114]

[0115] 2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-5-fluoro-1H-benzimidazole

[0116] Example 6 was prepared by the following procedure.

[0117]5-[2-(4-Benzyl-piperidin-1-yl)-ethyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione:

[0118] Following the procedure described in S. Danishefsky and R. K.Singh, J. American Chemical Society, 97:3239-3241(1975), a mixture of0.5 g of 4-benzylpiperidine, 10 mL of toluene, and 0.5 g of6,6-dimethyl-5,7-dioxa-spiro[2.5]octane-4,8-dione was stirred for 20 h,cooled, and the white solid product collected by filtration and driedunder vacuum. The yield of5-[2-(4-benzyl-piperidin-1-yl)-ethyl]-2,2-dimethyl-[1,3]dioxane-4,6-dionewas 0.94 g.

[0119] 2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-5-fluoro-1H-benzimidazole:

[0120] A mixture of 0.08 g of5-[2-(4-benzyl-piperidin-1-yl)-ethyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione,10 mL of diglyme and 4 drops of conc hydrochloric acid was heated toreflux for 18 h. The mixture was cooled, and partitioned between diluteaqueous ammonium hydroxide and dichloromethane. The combined extractswere dried over magnesium sulfate and concentration under reducedpressure. The residue was purified by preparative TLC eluting with 70:30chloroform:methanol. The major band (UV visualization) was2-[3-(4-benzyl-piperidin-1-yl)-propyl]-5-fluoro-1H-benzimidazole (80mg): MS (m+1)=352.4; ¹H NMR (400 MHz, CDCl₃) 9.2 (br, 1H), 7.32 (m, 2H),7.25 (m, 2H), 7:2 (m, 2H), 7.15 (m, 1H), 6.9 (dd, 1H), 3.1 (m, 4H), 2.65(m, 2H), 2.6 (m, 2H), 2.1 (m, 2H), 2.0 (m, 2H), 1.8 (m, 2H), 1.7 (m,1H), 1.5 (m, 2H).

Example 7

[0121]

[0122]2-{3-[4-(4-Chloro-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole

[0123] Example 7 was prepared by the following procedure.

[0124] 4-(4-Chloro-benzylidene)-piperidine-1-carboxylic Acid Tert-ButylEster:

[0125] To a stirred solution of 2 g of 4-oxo-piperidine-1-carboxylicacid tert-butyl ester and 3.5 g of diethyl 4-chlorobenzylphosphonate in10 mL of 1,3-dimethyl-2-imidazolidinone dried over 4 Å mol sieves wasadded 0.50 g of 60% sodium hydride oil dispersion. The mixture wasallowed to stir overnight, diluted with 200%L of water and extractedwith 3×100 mL of ether. Combined extracts were dried over magnesiumsulfate and concentrated under reduced pressure. Low pressurechromatography over silica gel eluting with a gradient of 5:95 ethylacetate:hexane to 1:5 ethyl acetate:hexane gave 2 g of4-(4-chloro-benzylidene)-piperidine-1-carboxylic acid tert-butyl esteras a colorless oil.

[0126] 5-(4-Chloro-benzyl)-2-aza-bicyclo[2.2.2]octane-2-carboxylic AcidEthyl Ester:

[0127] A solution of 2 g of4-(4-chloro-benzylidene)-piperidine-1-carboxylic acid tert-butyl esterand 0.5 g of 5% platinum on carbon in 100 mL of ethanol was allowed tostir overnight under 1 atm of hydrogen. The catalyst was filtered offand the solution concentrated to give 2 g of4-(4-chloro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester as anoil.

[0128] 4-(4-Chloro-benzyl)-piperidine:

[0129] A mixture of 2 g of 4-(4-chloro-benzyl)-piperidine-1-carboxylicacid tert-butyl ester, dioxane (1.5 mL), and 3N hydrochloric acid (1.0mL, 4 equiv.) was heated at reflux for 3.5 hours. The cooled mixture wasmade basic with saturated sodium carbonate solution and extracted withchloroform (3×10 mL). The combined extracts were dried over magnesiumsulfate and concentrated under reduced pressure. The crude product (1.2g) was an oil.

[0130]2-{3-[4-(4-Chloro-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole:

[0131] Steps 4 and 5 were performed in a similar manner to Example 4,but substituting 4-(4-chloro-benzyl)-piperidine for 4-benzylpiperidinein Step 4. Purification by chromatography eluting with 90:10 CHCl₃:MeOHgave 2-{3-[4-(4-chloro-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole:MS (m+1)=369; ¹H NMR (400 MHz, CDCl₃) 9.75 (br, 1H), 7.7 (br, 1H), 7.5(br, 1H), 7.4 (d, 2H), 7.32 (d, 2H), 7.2 (d, 2H), 3.1 (m, 4H), 2.65 (m,2H), 2.6 (m, 2H), 2.1 (m, 2H), 2.0 (m, 2H), 1.75 (d, 2H), 1.7 (m, 1H),1.5 (m, 2H).

Example 8

[0132]

[0133]2-{3-[4-(4-Methyl-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole

[0134] Example 8 was prepared in a similar manner to Example 6, butsubstituting 4-(4-methyl-benzyl)-piperidine for4-(4-chloro-benzyl)-piperidine in Step 4. Purification by chromatographyeluting with 90:10 CHCl₃:MeOH gave2-{3-[4-(4-methyl-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole: MS(m+1)=348.5; ¹H NMR (400 MHz, CDCl₃) 9.75 (br, 1H), 7.7 (br, 1H), 7.5(br, 1H), 7.4 (m, 2H), 7.3-7.2 dd, 4H), 3.1 (m, 4H), 2.65 (m, 2H), 2.6(m, 2H), 2.4 (s, 3H), 2.1 (m, 2H), 2.0 (m, 2H), 1.8 (d, 2H), 1.7 (m,1H), 1.5 (m, 2H).

Example 9

[0135]

[0136] 2-[3-(4-Benzyl-piperidin-1-yl)-1-methyl-propyl]-1H-benzimidazole

[0137] Example 9 was prepared by the following procedure.

[0138] 3-(1H-Benzimidazol-2-yl)-butan-1-ol:

[0139] Following the general procedure described in A. R. Friedman, D.S. Payne and A. R. Day, J. Heterocyclic Chemistry, 3:257-259(1966), amixture of 9 g of 1,2-phenylenediamine dihydrochloride and 7 g of2-methylbutyrolactone in 60 mL of 4N hydrochloric acid was heated toreflux for 4 days, 1 teaspoon of decolorizing carbon added, and afteranother 15 min reflux, filtered hot. The filtrate was concentrated underreduced pressure to near dryness, the residue made basic (pH 8) withammonium hydroxide and extracted into 3×100 mL of ethyl acetate. Thecombined extracts were dried over magnesium sulfate and concentratedunder reduced pressure. After drying under vacuum, 12 g of3-(1H-benzimidazol-2-yl)-butan-1-ol was obtained as a resin.

[0140]3-[2-(3-Hydroxy-1-methyl-propyl)-benzimidazol-1-yl]-propionitrile:

[0141] A mixture of 6 g of 3-(1H-benzimidazol-2-yl)-butan-1-ol, 20 mL ofacetic acid and 5 mL of acetic anhydride was heated to reflux for 4 h.The mixture was cooled, concentrated, added 100 mL of methanol and againconcentrated under reduced pressure. Azeotropically dried under reducedpressure with 200 mL of toluene, then under vacuum overnight. To astirred solution of the crude acetate of3-(1H-benzimidazol-2-yl)-butan-1-ol, 8.3 g, in 250 mL of acetonitrilewas added 5 mL of acrylonitrile, 2 drops of 1M tetrabutylammoniumfluoride in THF and dropwise ION NaOH until basic. After heating to 85°C. for 16 h, the mixture was cooled, concentrated under reducedpressure, and partitioned between 2×300 mL of ethyl acetate and 100 mLof water. The combined extracts were dried over magnesium sulfate andconcentrated under reduced pressure. The residue was triturated with 25mL of ethyl acetate, cooled in an ice bath and filtered. The resultingwhite solid, 3.0 g, was3-[2-(3-hydroxy-1-methyl-propyl)-benzimidazol-1-yl]-propionitrile.

[0142] 3-[2-(1-Methyl-3-oxo-propyl)-benzoimidazol-1-yl]-propionitrile:

[0143] To a stirred solution of 1.0 mL of oxalyl chloride in 20 mL ofmethylene chloride cooled to −78° C. was added 2 mL of anhydrous DMSO.After 15 min, a solution of 1 g of3-[2-(3-hydroxy-1-methyl-propyl)-benzoimidazol-1-yl]-propionitrile in 20mL of anhydrous DMSO and 50 mL of methylene chloride was added keepingthe temperature below −50° C. After 10 min, 10 mL of triethyl amine wasadded and the mixture allowed to warm to room temperature. After 15 min,the mixture was diluted with 250 mL of water, shaken and separated. Theorganic layer was dried over magnesium sulfate and concentrated underreduced pressure. The crude3-[2-(3-oxo-propyl)-benzimidazol-1-yl]-propionitrile was an amber resin(1.2 g), and contained only traces of the starting alcohol by TLC (90:10methylene chloride:methanol).

[0144]3-{2-[3-(4-Benzyl-piperidin-1-yl)-1-methyl-propyl]-benzimidazol-1-yl}-propionitrile:

[0145] A mixture of 0.3 g of 4-benzyl-piperidine, 0.2 g of3-[2-(3-oxo-propyl)-benzimidazol-1-yl]-propionitrile, 5 mL of1,2-dichloroethane and 0.3 g of sodium triacetoxyborohydride was stirredat room temperature for 24 h. The reaction mixture was diluted with 50mL chloroform and 10 mL saturated aqueous Na₂CO₃ and the layersseparated. The aqueous layer was extracted with 2×25 mL of chloroformand the combined organic layers dried over magnesium sulfate andconcentrated under reduced pressure. Low pressure chromatography elutingwith a gradient of 70:30 ethyl acetate:methanol to 80:20:2 ethylacetate:methanol:triethylamine gave 205 mg of3-{2-[3-(4-benzyl-piperidin-1-yl)-1-methyl-propyl]-benzimidazol-1-yl}-propionitrileas a gum.

[0146]2-[3-(3-Benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-1H-benzimidazole:

[0147] A mixture of 0.2 g of3-{2-[3-(4-benzyl-piperidin-1:-yl)-1-methyl-propyl]-benzimidazol-1-yl}-propionitrile,10 mL of tert-butanol and Ig of potassium tert-butoxide was heated toreflux for 10 min. Conversion was complete by TLC (80:20:1 ethylacetate:methanol:triethylamine). The mixture was cooled, diluted with 10mL of saturated sodium bicarbonate and concentrated. The residue waspartitioned between 3×100 mL of chloroform and 50 mL of water. Afterdrying over magnesium sulfate and concentration under reduced pressure,the residue was purified by preparative TLC eluting with 450:50:10chloroform:methanol:ammonium hydroxide. The major band (UVvisualization) was2-[3-(4-benzyl-piperidin-1-yl)-1-methyl-propyl]-1H-benzimidazole (82mg): MS (m+1)=348.5; ¹H NMR (400 MHz, CDCl₃) 7.42 (s, 2H), 7.3 (m, 2H),7.25 (m, 1H), 7.2 (m, 4H), 3.25 (m, 1H), 3.08 (m, 2H), 2.65 (d, 2H), 2.6(m, 1H), 2.5 (m, 1H), 2.1 (m, 2H), 1.95 (m, 2H), 1.8 (d, 2H), 1.7 (m,1H), 1.5 (d, 3H), 1.5 (m, 1H).

Example 10

[0148]

[0149] 2-[3-(4-Benzyl-piperidin-1-yl)-butyl]-1H-benzimidazole

[0150] Example 10 was prepared by the following procedure.

[0151] 4-(1H-Benzimidazol-2-yl)-butan-2-ol:

[0152] A mixture of 8 g of 1,2-phenylenediamine and 6.6 g of 4-pentenoicacid in 50 mL of 4N hydrochloric acid was heated to reflux for 18 hours,cooled in an ice bath, made basic (pH=8) with ammonium hydroxide andextracted into 3×100 mL of ethyl acetate. The combined extracts weredried over magnesium sulfate and concentrated under reduced pressure.After drying under vacuum, lOg of 4-(1H-benzimidazol-2-yl)-butan-2-olwas obtained as a thick oil which slowly crystallized.

[0153] Acetic Acid3-[1-(2-cyano-ethyl)-1H-benzoimidazol-2-yl]-1-methyl-propyl Ester:

[0154] A mixture of 6 g of 4-(1H-benzimidazol-2-yl)-butan-2-ol, 20 mL ofacetic acid and 5 mL of acetic anhydride was heated to reflux for 6 h.The mixture was cooled, concentrated, added 100 mL of methanol and againconcentrated under reduced pressure. Azeotropic drying under reducedpressure with 200 mL of toluene, then under vacuum overnight gave 8.3 gof the acetate of 4-(1H-benzimidazol-2-yl)-butan-2-ol as a crystallinesolid. To a stirred solution of 7.5 g of the acetate of4-(1H-benzimidazol-2-yl)-butan-2-ol in 250 mL of acetonitrile was added5 mL of acrylonitrile, 2 drops of 1M tetrabutylammonium fluoride in THFand dropwise ION NaOH until basic. After heating to 85° C. for 46 h, themixture was cooled, concentrated under reduced pressure, and partitionedbetween 2×300 mL of ethyl acetate and 100 mL of water. The combinedextracts were dried over magnesium sulfate and concentrated underreduced pressure. Purification of the residue by low pressurechromatography eluting with ethyl acetate gave 9.2 g of the acetateester of 3-[2-(3-hydroxy-butyl)-benzimidazol-1-yl]-propionitrile as aresin.

[0155] 3-[2-(3-Hydroxy-butyl)-benzimidazol-1-yl]-propionitrile:

[0156] A mixture of 8.1 g of the acetate ester of3-[2-(3-hydroxy-butyl)-benzimidazol-1-yl]-propionitrile (Product of Step2), 100 mL of methanol, 25 mL of water and 1.2 g of lithium hydroxidemonohydrate was stirred for 12 h at room temperature, concentrated underreduced pressure diluted with 50 mL of water and extracted with 3×100 mLportions of ethyl acetate. Combined extracts were dried over magnesiumsulfate, concentrated under reduced pressure and dried azeotopicallywith toluene. Drying under vacuum gave 7.6 g of3-[2-(3-hydroxy-butyl)-benzimidazol-1-yl]-propionitrile as a thick oil.

[0157] 3-[2-(3-Oxo-butyl)-benzimidazol-1-yl]-propionitrile:

[0158] To a stirred solution of 1.0 mL of oxalyl chloride in 30 mL ofmethylene chloride cooled to −78° C. was added 2 mL of anhydrous DMSO.After 10 min, a solution of 2.1 g of3-[2-(3-hydroxy-butyl)-benzimidazol-1-yl]-propionitrile in 150 mL ofdichloromethane was added keeping the temperature below −50° C. After 10min, 10 mL of triethyl amine was added and the mixture allowed to warmto room temperature. After 15 min, the mixture was diluted with 250 mLof water, shaken and separated. The organic layer was dried overmagnesium sulfate and concentrated under reduced pressure. Drying undervacuum gave 2.2 g of 3-[2-(3-oxo-butyl)-benzimidazol-1-yl]-propionitrileas an amber resin.

[0159]3-{2-[3-(4-Benzyl-piperidin-1-yl)-butyl]-benzimidazol-1-yl}-propionitrile:

[0160] A mixture of 0.3 g of 4-benzyl-piperidine, 0.24 g of3-[2-(3-oxo-butyl)-benzimidazol-1-yl]-propionitrile, 5 mL of1,2-dichloroethane and 0.3 g of sodium triacetoxyborohydride was stirredat room temperature for 3 days. The reaction mixture was diluted with 50mL chloroform and 10 mL saturated aqueous Na₂CO₃ and the layersseparated. The aqueous layer was extracted with 2×25 mL of chloroformand the combined organic layers dried over magnesium sulfate andconcentrated under reduced pressure. Low pressure chromatography elutingwith a gradient of 80:20 ethyl acetate:methanol to 80:20:5 ethylacetate:methanol:triethylamine gave 320 mg of3-{2-[3-(4-benzyl-piperidin-1-yl)-butyl]-benzimidazol-1-yl}-propionitrileas a resin.

[0161] 2-[3-(4-Benzyl-piperidin-1-yl)-butyl]-1H-benzimidazole:

[0162] A mixture of 0.32 g of3-{2-[3-(4-benzyl-piperidin-1-yl)-butyl]-benzimidazol-1-yl}-propionitrile,10 mL of tert-butanol and 1 g of potassium tert-butoxide was heated toreflux for 10 min. Conversion was complete by TLC (80:20:1 ethylacetate:methanol:triethylamine). The mixture was cooled, diluted with 10mL of saturated sodium bicarbonate and concentrated. The residue waspartitioned between 3×100 mL of chloroform and 50 mL of water. Afterdrying over magnesium sulfate and concentration under reduced pressure,the residue was purified by preparative TLC eluting with 90:10:2chloroform:methanol:ammonium hydroxide. The major band (UVvisualization) was2-[3-(4-benzyl-piperidin-1-yl)-butyl]-1H-benzimidazole (250 mg): MS(m+1)=348.5; ¹H NMR (400 MHz, CDCl₃) 7.42 (s, 2H), 7.3 (m, 2H), 7.25 (m,1H), 7.2 (m, 4H), 3.25 (m, 1H), 3.0 (m, 2H), 2.8 (d, 2H), 2.65 (m, 2H),2.5 (m, 2H), 2.1 (m, 2H), 1.6 (d, 2H), 1.3 (m, 1H), 1.2 (d, 3H), 1.0 (m,1H).

Example 11

[0163]

[0164] 2-[3-(4-Benzyl-3-methyl-piperidin-1-yl)-propyl]-1H-benzimidazole

[0165] Example 11 was prepared by the following procedure.

[0166] 1-Benzyl-4-benzylidene-3-methyl-piperidine:

[0167] To a stirred solution of 2.1 g of1-benzyl-3-methyl-piperidin-4-one and 2.5 g of diethyl benzylphosphonatein 5 mL of 1,3-dimethyl-2-imidazolidinone dried over 4 Å mol sieves wasadded 0.50 g of 60% sodium hydride oil dispersion. The mixture wasallowed to stir 2 days, diluted with 400 mL of water and extracted with3×50 mL of ether. Combined extracts were dried over magnesium sulfateand concentrated under reduced pressure. Low pressure chromatographyover silica gel eluting with a gradient of 5:95 ethyl acetate:hexane to1:4 ethyl acetate:hexane gave 2.7 g of1-benzyl-4-benzylidene-3-methyl-piperidine as a colorless oil.

[0168] 4-Benzyl-3-methyl-piperidine:

[0169] A solution of 2.7 g of 1-benzyl-4-benzylidene-3-methyl-piperidineand 2 g of 20% palladium hydroxide on carbon in 125 mL of ethanol wasshaken 3 days under 55 psi of hydrogen. The catalyst was filtered offand the solution concentrated to give 2 g of a mixture of cis andtrans-4-benzyl-3-methyl-piperidine as an oil.

[0170] 2-[3-(4-Benzyl-3-methyl-piperidin-1-yl)-propyl]-1H-benzimidazole:

[0171] Steps 4 and 5 were performed in a similar manner to Example 5,but substituting 4-benzyl-3-methyl-piperidine for 4-benzylpiperidine inStep 4. Purification by chromatography eluting with 225:20:5chloroform:methanol:ammonium hydroxide gave cis and trans2-[3-(4-benzyl-3-methyl-piperidin-1-yl)-propyl]-1H-benzimidazole asclose moving bands: MS (m+1)=348.5; ¹H NMR (400 MHz, CDCl₃) 7.58 (d,2H), 7.2-7.0 (m, 7H), 3.0 (m, 4H), 2.5 (m, 4H), 2.0 (m, 2H), 1.6 (m,2H), 1.1 (2×d, 3H), 1.0 (m, 2H).

Example 12

[0172]

[0173]N-[2-(4-Benzyl-piperidin-1-ylmethyl)-3If-benzoimidazol-5-yl]-methanesulfonamide

[0174] Example 12 was prepared by the following general procedure.

[0175] To a solution of 4-benzylpiperidine (1.0 g, 5.7 mmol) in DMF (20mL) was added ethylbromoacetate (637 μL, 5.7 mmol) and the reactionmixture was stirred at room temperature for 4 h. The reaction mixturewas partitioned between EtOAc and aqueous NaHCO₃, the organic layer wasdried over Na₂SO₄, filtered and concentrated. The crude oil was purifiedby silica gel chromatography (gradient elution, 4:1 hexanes:EtOAc toEtOAc) to give the ethyl ester.

[0176] The ethyl ester (700 mg, 2.6 mmol) was dissolved in 6N HCl (5 mL)and heated to reflux for 1 h. The reaction mixture was cooled andconcentrated to give

[0177] Intermed. 15 as a white solid.

[0178] To a solution of carboxylic acid Intermed. 15 (117 mg, 0.5 mmol)in DMF (3 mL) was added EDC (96 mg, 0.5 nmml), HOBt (68 mg, 0.5 mmol),and N-(3,4-diamino-phenyl)-methanesulfonamide (100 mg, 0.5 mmol). Thereaction mixture was stirred at room temperature for 1 h followed byquenching with aqueous NaHCO₃ and EtOAc. The layers were separated andthe organic was washed twice with water, dried over NaSO₄, filtered andconcentrated. The crude oil was dissolved in AcOH and heated to refluxfor 15 min. The reaction mixture was cooled, concentrated and purifiedby reverse-phase HPLC to giveN-[2-(4-Benzyl-piperidin-1-ylmethyl)-3H-benzoimidazol-5-yl]-methanesulfonamide(90 mg): ¹H NMR (300 MHz, CD₃OD) δ 7.82 (d, 1H), 7.77 (s,1H), 7.49(d,1H), 7.32-7.17 (m, 5H), 4.92 (s, 2H), 3.70 (d, 2H), 3.02 (s, 2H),2.60 (d, 2H), 2.00-1.88 (m, 3H), 1.70 (m, 2H); mass spectrum m/z 399[(M+H)⁺; calcd for C₂₁H₂₇N₄O₂S: 399].

What is claimed is:
 1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R₁ is i)2-benzimidazole, 2-imidazopyridine, 2-indole, purine, or 2-quinazoline,each optionally substituted with one to five substituents, eachsubstituent independently being chloro, fluoro, bromo, C₁-C₄alkyl,trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, or carboxy; or ii)phenyl, optionally substituted with one to five substituents, eachsubstituent independently being chloro, fluoro, bromo, C₁-C₄alkyl,trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, or carboxy; R₂ is a)2-benzimidazole, 2-imidazopyridine, 2-indole, purine, or 2-quinazoline,each optionally substituted with one to five substituents, eachsubstituent independently being chloro, fluoro, bromo, C₁-C₄alkyl,trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, or carboxy; or b)phenyl, optionally substituted with one to five substituents, eachsubstituent independently being chloro, fluoro, bromo, C₁-C₄alkyl,trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, or carboxy; When R₁ isi, then R₂ is b; when R₁ is ii, then R₂ is a; When R₁ or R₂ is2-benzimidazole, respective L₁ or L₂ is not C₁-C₂alkyl, except when R₁or R₂ is hydroxy-substituted 2-benzimidazole, respective L₁ or L₂includes C₁-C₂alkyl L₁ and L₂ are independently C₁-C₄alkyl,C₁-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy, aminoC₁-C₄alkyl,hydroxyC₁-C₄alkyl, carbonyl, cycloC₃-C₆alkyl or aminocarbonyl; andoptionally substituted at any of the 2, 3, 5, or 6 positionsindependently with X, wherein X is hydroxy, amino, C₁-C₄alkylamino,di(C₁-C₄)alkylamino, C₁-C₄alkyl, ester, carbamate, carbonate, or ether.2. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, wherein R₁ is 2-imidazopyridine, optionally substitutedwith one to five substituents, each substituent independently beingchloro, fluoro, bromo, C₁-C₄alkyl, trifluoromethyl,C₁-C₄alkylsulfonamide, hydroxy, or carboxy; R₂ is phenyl, optionallysubstituted with one to five substituents, each substituentindependently being chloro, fluoro, bromo, C₁-C₄alkyl, trifluoromethyl,C₁-C₄alkylsulfonamide, hydroxy, or carboxy; L₁ and L₂ are independentlyC₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy, aminoC₁-C₄alkyl,hydroxyC₁-C₄alkyl, carbonyl, cycloC₃-C₆alkyl or aminocarbonyl; andoptionally substituted at any of the 2, 3, 5, or 6 positionsindependently with X, wherein X is hydroxy, amino, C₁-C₄alkylamino,di(C₁-C₄)alkylamino, C₁-C₄alkyl, ester, carbamate, carbonate, or ether.3. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, wherein R₁ is purine, optionally substituted with one tofive substituents, each substituent independently being chloro, fluoro,bromo, C₁-C₄alkyl, trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, orcarboxy; R₂ is phenyl, optionally substituted with one to fivesubstituents, each substituent independently being chloro, fluoro,bromo, C₁-C₄alkyl, trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, orcarboxy; L₁ and L₂ are independently C₁-C₄alkyl, C₁-C₄alkenyl,C₁-C₄alkynyl, C₁-C₄alkoxy, aminoC₁-C₄alkyl, hydroxyC₁-C₄alkyl, carbonyl,cycloC₃-C₆alkyl or aminocarbonyl; and optionally substituted at any ofthe 2, 3, 5, or 6 positions independently with X, wherein X is hydroxy,amino, C₁-C₄alkylamino, di(C₁-C₄)alkylamino, C₁-C₄alkyl, ester,carbamate, carbonate, or ether.
 4. The compound according to claim 1 ora pharmaceutically acceptable salt thereof, wherein R₁ is2-benzimidazole, optionally substituted with one to five substituents,each substituent independently being chloro, fluoro, bromo, C₁-C₄alkyl,trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, or carboxy; R₂ isphenyl, optionally substituted with one to five substituents, eachsubstituent independently being chloro, fluoro, bromo, C₁-C₄alkyl,trifluoromethyl, C₁-C₄alkylsulfonamide, hydroxy, or carboxy; L₁ is notC₁-C₂alkyl, except when R₁ is hydroxy-substituted 2-benzimidazole, L₁includes C₁-C₂alkyl; L₁ and L₂ are independently C₁-C₄alkyl,C₁-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy, aminoC₁-C₄alkyl,hydroxyC₁-C₄alkyl, carbonyl, cycloC₃-C₆alkyl or aminocarbonyl; andoptionally substituted at any of the 2, 3, 5, or 6 positionsindependently with X, wherein X is hydroxy, amino, C₁-C₄alkylamino,di(C₁-C₄)alkylamino, C₁-C₄alkyl, ester, carbamate, carbonate, or ether.5. The compound according to claim 1, wherein said compound is2-(4-Benzyl-piperidin-1-ylmethyl)-imidazo[4,5-b]pyridine;8-(4-Benzyl-piperidin-1-ylmethyl)-purine;2-(4-Benzyl-piperidin-1-ylmethyl)-imidazo[4,5-c]pyridine;2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-1H-benzimidazole;2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-imidazo[4,5-b]pyridine;2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-5-fluoro-1H-benzimidazole;2-{3-[4-(4-Chloro-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole;2-{3-[4-(4-Methyl-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole;2-[3-(4-Benzyl-piperidin-1-yl)-1-methyl-propyl]-1H-benzimidazole;2-[3-(4-Benzyl-piperidin-1-yl)-butyl]-1H-benzimidazole;2-[3-(4-Benzyl-3-methyl-piperidin-1-yl)-propyl]-1H-benzimidazole; orN-[2-(4-Benzyl-piperidin-1-ylmethyl)-3H-benzoimidazol-5-yl]-methanesulfonamide.6. The compound according to claim 1, wherein said compound is


7. A pharmaceutical composition comprising an inert carrier and aneffective amount of a compound according to claim
 1. 8. Thepharmaceutical composition according to claim 7 useful for the treatmentof pain.
 9. The pharmaceutical composition according to claim 7 usefulfor the treatment of migraine, depression, anxiety, schizophrenia,Parkinson's disease, or stroke.
 10. A method of treating pain comprisinga step of administering to one in need of such treatment an effectiveamount of a compound according to claim
 1. 11. A method of treatingmigraine, depression, anxiety, schizophrenia, Parkinson's disease, orstroke comprising a step of administering to one in need of suchtreatment an effective amount of a compound according to claim 1.